COVID-19 News: Californian Study Shows That Antiviral Activity Of The Lectin Griffithsin Against SARS-Cov-2 Is Enhanced By Presence Of Membrane Proteins.

COVID-19 News: The ongoing battle against the relentless SARS-CoV-2 virus has witnessed significant strides in vaccine development and monitoring techniques. However, the virus's persistent mutations and immune escape mechanisms demand innovative prophylactic treatments. In this context, Griffithsin, a protein derived from red algae Griffithsia, has emerged as a promising candidate. Recent research at the University of California Merced that is covered in this COVID-19 News report, sheds light on Griffithsin's enhanced antiviral activity against SARS-CoV-2, particularly when confronted with membrane proteins.


Structure and glycosylation of the three SARS-CoV-2 structural proteins. (A) Simplified depiction of SARS-CoV-2 lentiviral pseudovirions (left) versus SARS-CoV-2 coronavirus virions (right). HIV lentivirions incorporate numerous features into their viral particles, as they must carry the machinery necessary to reverse-transcribe the lentiviral RNA genome and incorporate it into the host DNA genome. In contrast, coronaviral particles only incorporate the structural proteins M, N, and E, in addition to the spike protein. Spike, M, and E proteins are present on the surface of coronavirus virions, while the surfaces of lentiviral pseudovirions are essentially bare of any protein aside from spike glycoprotein. (B) M protein dimeric structure, with 8 potential N-linked glycosylation sites shown in red. The M protein is the most highly expressed protein on the surface of the SARS-CoV-2 virion and exists as a homodimer. The 2 glycans that are on the extraviral side of the virion and are potentially accessible for DC-SIGN lectin receptor recognition are depicted as space-filling models. The glycan at N216 is on a superimposed loop to complete the structure of the database (PDB ID: 7VGR). (C) The N protein exists as a homodimer and is localized to the interior of the virion. It is not anticipated to undergo glycosylation. Rather, it mediates viral RNA genome packaging and regulates host immune responses (PDB ID: 8FG2). (D) SWISS-Model predicted structure of the SARS-CoV-2 E-protein. The E protein exists as a homopentamer on the viral surface and has two expected glycan sites, depicted in red. Glycan N66 is closer to the extraviral side of the viral membrane and is thus depicted as a space-filling model.

Griffithsin: A Broad-Spectrum Antiviral Agent
Griffithsin, with its 121-amino acid sequence and Jacalin-like lectin fold, exhibits broad-spectrum binding to glycoproteins of various viruses. It has proven effective against coronaviruses like SARS-CoV and Ebolavirus, demonstrating its potential as a versatile antiviral agent.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820936/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910741/
 
Cross-Linking Activity and Binding Dynamics
Griffithsin's bivalent sugar-binding capability, highlighted by cross-linking target proteins, is explored. The artic le underscores the importance of this activity in inhibiting various viruses, including HIV-1. This leads to an investigation into Griffithsin's potential to prevent SARS-CoV-2 entry by cross-linking spike proteins.
 
Targeting Spike Protein-Mediated Infection
The primary focus on Griffithsin has been its ability to prevent spike protein-mediated infection through the hACE2 receptor, inhibiting direct infection. However, the study recognizes the often-overlooked trans-infection facilitated by attachment receptors such as DC-SIGN. This revelation prompts a deeper exploration into the structural facets of both SARS-CoV-2 and Griffithsin to understand their interplay.
 
Examining Structural Facets: M Protein's Influence
The study delves into how the presence of the coronaviral M protein affects Griffithsin's inhibition of direct infection. Surprisingly, Griffithsin exhibits superior inhibitory activity when the M protein is present, offering insights into its effectiveness against authentic SARS-CoV-2 compared to pseudotyped viruses lacking M protein. This finding suggests a potential avenue for developing novel antiviral strategies.
 
Omicron Variant Challenges and Vaccine Dynamics
The article shifts its focus to the recent challenges posed by the Omicron variant, which has showcased a high mutation rate in its spike protein, leading to breakthrough infections even in individuals with multiple vaccine doses. The ever-evolving landscape of COVID-19 variants necessitates constant adjustments to booster vaccines. Furthermore, vaccine hesitancy and varying degrees of immunodeficiency underscore the importance of exploring alternative preventative treatments.
 
Griffithsin's Unique Properties and Variants
A detailed examination of Griffithsin's properties reveals its potential as a prophylactic agent. With low toxicity, stability in diverse conditions, and the ability to withstand freeze-thaw cycles, Griffithsin emerges as an adaptable candidate. The study introduces the M78Q variant, addressing spontaneous oxidation concerns and undergoing clinical trials as a prophylactic nasal spray against SARS-CoV-2.
 
Comparative Analysis of Griffithsin Variants
The study goes beyond previous research by comparing the inhibitory capacities of different Griffithsin variants against SARS-CoV-2 pseudoviral infections. While the M78Q mutation shows increased potency, the investigation seeks to understand the nuances between wild-type Griffithsin, M78Q-Griffithsin, and a cross-linking variant (GLG-3A). This comparative analysis aims to refine our understanding of Griffithsin's role in inhibiting viral entry.
 
Structural Disparities and Viral Architecture
The study also examines the disparities in Griffithsin's inhibition between lentiviral pseudovirions and authentic SARS-CoV-2 coronaviral particles. Viral architecture, assay read-out methods, and differences in viral MOI are considered as potential factors influencing Griffithsin's antiviral potency. A comprehensive exploration of these aspects provides valuable insights for future research directions.
 
DC-SIGN and Trans-Infection Dynamics
Understanding the role of lectin receptors, particularly DC-SIGN, in facilitating trans-infection becomes crucial. The study hypothesizes Griffithsin as a potential competitive inhibitor against DC-SIGN-mediated trans-infection. However, experimental results challenge this hypothesis, revealing that Griffithsin may not act as a viable inhibitor of DC-SIGN-mediated trans-infection, prompting further investigations into alternative attachment receptors.
 
Influence of Structural Proteins on Infection
The presence of additional structural proteins, M, N, and E, in SARS-CoV-2 virions raises questions about their influence on viral infectivity. Contrary to expectations, the N and E proteins do not significantly enhance trans-infectivity. Surprisingly, the M protein's presence amplifies susceptibility to Griffithsin inhibition, offering a potential explanation for the protein's superior efficacy against authentic SARS-CoV-2.
 
Implications for Future Antiviral Treatments
The comprehensive study concludes by emphasizing the need for further research to quantify the M protein's role in Griffithsin binding and inhibition. It envisions the development of Griffithsin variants and prophylactic protocols tailored to combat future SARS-CoV-2 strains. The intricate interplay between Griffithsin and the virus's structural components opens new avenues for targeted antiviral treatments.
 
Conclusion: Charting the Course Forward
In the relentless pursuit of effective COVID-19 prophylactics, Griffithsin emerges as a formidable contender. Its multifaceted inhibitory capabilities, especially against the M protein, provide a foundation for future research. The article not only bridges existing gaps in understanding but also lays the groundwork for refining Griffithsin-based prophylactic treatments against the ever-evolving landscape of SARS-CoV-2 variants. As the pandemic persists, this study contributes invaluable insights for charting the course forward in the ongoing battle against COVID-19.
 
The study findings were published in the peer reviewed journal: Viruses.
https://www.mdpi.com/1999-4915/15/12/2452
 
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